Diisopropylethylamine → (2-{1-benzenesulfonyl-4-[1-(2-cyano-ethyl)-piperidin-4-ylamino]-1H-pyrrolo[2,3-b]pyridin-5-ylcarbamoyl}-ethyl)-carbamic acid 9H-fluoren-9-ylmethyl ester

HRID 1257605노트

반응식

HRID 1257605 반응식
[C:1]([NH:18][CH2:19][CH2:20][C:21](O)=[O:22])([O:3][CH2:4][CH:5]1[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[C:11]2[C:6]1=[CH:7][CH:8]=[CH:9][CH:10]=2)=[O:2].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(C(C)C)CC)(C)C.[NH2:57][C:58]1[C:59]([NH:76][CH:77]2[CH2:82][CH2:81][N:80]([CH2:83][CH2:84][C:85]#[N:86])[CH2:79][CH2:78]2)=[C:60]2[CH:66]=[CH:65][N:64]([S:67]([C:70]3[CH:75]=[CH:74][CH:73]=[CH:72][CH:71]=3)(=[O:69])=[O:68])[C:61]2=[N:62][CH:63]=1>CN(C=O)C>[CH:7]1[C:6]2[CH:5]([CH2:4][O:3][C:1](=[O:2])[NH:18][CH2:19][CH2:20][C:21](=[O:22])[NH:57][C:58]3[C:59]([NH:76][CH:77]4[CH2:78][CH2:79][N:80]([CH2:83][CH2:84][C:85]#[N:86])[CH2:81][CH2:82]4)=[C:60]4[CH:66]=[CH:65][N:64]([S:67]([C:70]5[CH:71]=[CH:72][CH:73]=[CH:74][CH:75]=5)(=[O:69])=[O:68])[C:61]4=[N:62][CH:63]=3)[C:17]3[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=3)[C:11]=2[CH:10]=[CH:9][CH:8]=1

참가 물질

6

반응물 4

HCID 81531DiisopropylethylamineHCID 2724630N-Fluorenylmethoxycarbonyl-I2-alanineHCID 9886157Methanaminium, N-((dimethylamino)(3H-1,2,3-triazolo(4,5-b)pyridin-3-yloxy)methylene)-N-methyl-, hexafluorophosphate(1-) (1:1)HCID 673456183-[4-(5-amino-1-benzenesulfonyl-1H-pyrrolo[2,3-b]pyridin-4-ylamino)-piperidin-1-yl]-propionitrile

생성물 1

HCID 67345405(2-{1-benzenesulfonyl-4-[1-(2-cyano-ethyl)-piperidin-4-ylamino]-1H-pyrrolo[2,3-b]pyridin-5-ylcarbamoyl}-ethyl)-carbamic acid 9H-fluoren-9-ylmethyl ester수율 97%

시약·촉매·용매 1

HCID 6228Dimethylformamide용매

반응 조건

온도
25 °C

실험 절차

Fmoc-beta-Alanine (3.1 g, 9.90 mmol), HATU (3.8 g, 9.90 mmol), and diisopropylethylamine (2.1 ml, 12.0 mmol) were added sequentially to a solution of 3-[4-(5-amino-1-benzenesulfonyl-1H-pyrrolo[2,3-b]pyridin-4-ylamino)-piperidin-1-yl]-propionitrile (4.2 g, 9.90 mmol) in DMF (100 ml) at 25° C. The reaction mixture was stirred for 14 h at 25° C., then was concentrated under reduced pressure. The residue was partitioned between half-saturated NaHCO3 (200 ml) and EtOAc (2×200 ml). the combined organic layers were dried over Mg2SO4, filtered, and the filtrate was concentrated under reduced pressure. Purification of the residue by column chromatography on silica gel (gradient: 0 to 7% CH3OH in CH2Cl2) afforded (2-{1-benzenesulfonyl-4-[1-(2-cyano-ethyl)-piperidin-4-ylamino]-1H-pyrrolo[2,3-b]pyridin-5-ylcarbamoyl}-ethyl)-carbamic acid 9H-fluoren-9-ylmethyl ester (6.89 g, 97%) as a white foam. LCMS (Method G, ESI): RT=0.85 min, m+H=718.5. 1H NMR (400 MHz, CDCl3, mixture of rotamers) δ 8.14 (t, J=10.3 Hz), 7.84 (s), 7.75 (dd, J=15.2, 7.5 Hz), 7.60-7.54 (m), 7.50 (d, J=4.1 Hz), 7.44 (t, J=7.8 Hz), 7.37 (t, J=7.4 Hz), 7.28 (t, J=5.8 Hz), 6.52 (t, J=4.7 Hz), 5.50 (d, J=11.4 Hz), 4.70 (s), 4.40 (s), 4.33 (d, J=7.1 Hz), 4.19 (t, J=6.6 Hz), 3.64 (td, J=13.3, 6.7 Hz), 3.51 (d, J=21.9 Hz), 3.39 (d, J=5.4 Hz), 2.80-2.47 (m), 2.35 (s), 2.30-2.07 (m), 1.93 (d, J=12.0 Hz), 1.51 (dt, J=13.5, 6.8 Hz).

후처리

  1. concentrationwas concentrated under reduced pressure
  2. customThe residue was partitioned between half-saturated NaHCO3 (200 ml) and EtOAc (2×200 ml)
  3. dry with materialthe combined organic layers were dried over Mg2SO4
  4. filtrationfiltered
  5. concentrationthe filtrate was concentrated under reduced pressure
  6. customPurification of the residue by column chromatography on silica gel (gradient: 0 to 7% CH3OH in CH2Cl2)

출처 및 근거

ORD 기록
ord-5fc5ca75c2244d9098538f60488cf4ce
출처 데이터셋
uspto-grants-2013_06
특허 번호
US08461328B2

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